Changes in cytosolic calcium ion concentrations ([Ca.sup.2+ ].sub.i) evoke a wide range of cellular responses. Intracellular Ca.sup.2+ -binding proteins are the key molecules in transducing Ca.sup.2+ signaling via enzymatic reactions or modulation of protein-protein interactions, some of which contribute to cell cycle events, and/or to cellular differentiation. Following stimulation by second messenger molecules, such as inositoltrisphosphate, [Ca.sup.2+ ].sub.i is briefly released from the endoplasmic reticulum into the surrounding cytoplasm. Similar processes take place in the dividing cell nucleus during breakdown of the nuclear membrane and segregation of chromatids at anaphase.
The calcium-binding domain of many proteins contains the high affinity Ca.sup.2+ -binding motif often referred to as the EF-hand. The EF-hand is characterized by a twelve amino acid residue-containing loop, flanked by two .alpha.-helices, orientated approximately 90.degree. with respect to one another. Aspartate (D) and glutamate (E) residues are usually found at positions 10 and 21, respectively, bordering the twelve amino acid loop. In addition, a conserved glycine residue in the central portion of the loop is found in most Ca.sup.2+ -binding EF-hand domains. Oxygen ligands within this domain coordinate the Ca.sup.2+ ion (Kretsinger, R. H. and Nockolds, C. E. (1973) J. Biol. Chem. 248:3313-3326).
The S100 proteins are a group of low molecular mass (approximately 10-12 kDa) acidic Ca.sup.2+ -binding proteins, so named after the solubility of the first isolated protein in 100% saturated ammonium sulfate. The most striking conserved feature of these proteins is the presence of an EF-hand. The S100 proteins have two Ca.sup.2+ -binding domains. One of these domains is a basic helix-loop-helix domain, the other domain is an acidic helix-loop-helix EF-hand (Kligman, D. and Hilt, D. C. (1988) Trends Biochem. Sci. 13:437-442). The EF-hand domain also encompasses a part of a region within S100 proteins which specifically identifies members of the S100 family of proteins which have a low affinity for Ca.sup.2+ ions (S100/ICaBP; PROSITE PS00303, SWISSPROT).
No specific enzymatic property has been ascribed to any of the proteins to date. The binding to calcium induces a conformational change in the S100 proteins, and this may then affect the secondary effector proteins. This mode of protein-protein interaction and modulation of the activity of the secondary effector protein is similar to that seen with calmodulin, another family of calcium-binding proteins containing the EF-hands. As the distribution of particular S100 proteins is dependent on specific cell types, the S100 proteins may be involved in transducing the signal of an increase in intracellular calcium in a cell type-specific fashion (Wu, T. et al. (1997) J. Biol. Chem. 272:17145-17153).
S100 beta (S100.beta.) is produced and secreted by glial cells in the central and peripheral nervous systems (Allore, R. J. et al. (1990) J. Biol. Chem. 265:15537-15543). The accumulation of S100.beta. in mature glial cells is associated with the microtubule network. S100.beta. promotes neuronal differentiation and survival but may be detrimental to cells if overexpressed. The selective overproduction has been implicated in the progression of the neuropathological changes in Alzheimer's disease which may involve mitotic protein kinases (Marshak, D. R. and Pena, L. A. (1992) Prog. Clin. Biol. Res. 379:289-307).
Adult T-cell leukaemia (ATL) is a mature T-cell malignancy which is caused by human T lymphotrophic virus type-1. Diminished surface expression of the T-cell receptor alpha beta (TCR.alpha..beta.+) complex is a specific feature of ATL cells. S100.beta. is not detectable in CD4+, TCR.alpha..beta. ATL cells, but is expressed in CD4-, CD8-, TCR .alpha..beta.+ leukaemic cells from four ATL patients. This suggested that increased levels of S100.beta. may be associated with the diminished surface expression of the TCRa, complex in ATL (Suzushima, H. et al. (1994) Leuk. Lymphoma 13:257-262).
Elevated serum levels of S100.beta. are associated with disseminated malignant melanoma metastases, suggesting that serum S100.beta. may be of value as a clinical marker for progression of metastatic melanoma (Henze, G. et al. (1997) Dermatology 194:208-212).
Messenger RNA levels encoding human calgizzarin (an S100-like protein), as well as those encoding phospholipase A.sub.2, are elevated in colorectal cancers compared with those of normal colorectal mucosa (Tanaka, M. et al. (1995) Cancer Lett. 89:195-200).
An intracellular calcium-binding protein has been isolated from rat peritoneum. This protein, MRP 14, is one of two migration inhibitory factor-related proteins that are expressed in peritoneal macrophages in the arthritis-susceptible Lewis/N rat (Imamichi, T. et al. (1993) Biochem. Biophys. Res. Comm. 194:819-825).
The discovery of two new human S100 proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of neuronal, vesicle trafficking, immunological, and neoplastic disorders.